SUMMARY ? PROJECT 3: MITF IN DRUG RESISTANCE AND METABOLISM IN MELANOMA Long Term Objective: The long-term objective of this study is too understand how stress from the tumor microenvironment, and from treatment with drug, alter melanoma cell phenotype and lead to a drug resistant and invasive phenotype. The study seeks to identify new leverage points that can be targeted to develop new drugs. The Unmet Medical Need: Estimates by the American Cancer Society (ACS) predict that in 2013 close to 80,000 new melanoma cases were diagnosed in the US, and almost 10,000 people were expected to die from the disease. Unlike many other cancers, melanoma occurs in all age groups, and is one of the most common malignancies in adults under 40. There is a pressing unmet medical need for new therapies to treat melanoma, especially because patients treated with BRAF inhibitors experience only short term benefit, the vast majority ultimately relapse as the tumor becomes resistant to drug. The Hypothesis: The primary hypothesis of the study is that adaptation two types of stress, (i) nutrient deprivation and (ii) and BRAF inhibition, evoke related molecular and metabolic adaptations in melanoma that lead to an invasive, tumor-initiating and drug-resistant phenotype. We pose two questions as Specific Aims: (1) What are the molecular mechanisms underlying the generation of phenotypically invasive, tumor-initiating or drug-resistant melanoma cells by the ATF4-MITF axis? (2) What metabolic changes accompany acquisition of tolerance to nutrient deprivation and resistance to BRAFi? The Research Team: The Project Leader and co-I are uniquely qualified to conduct the studies. Dr. Colin Goding is Professor at the Ludwig Institute for Cancer Research and Co-Director, Oxford Stem Cell Institute at the University of Oxford. Dr. Goding is one of the internationally recognized thought leaders in the field of melanoma. Dr. Jeffrey W. Smith has led a research team focused on defining central carbon metabolism in cancer for the past decade. The team's primary strategy has been to use isotopic tracers to quantify metabolic flux, a direct measure of activity of metabolic pathways. In collaboration with Dr. Andrei Osterman (leader of Core B), the group has published six key papers that lay the foundation for understanding regulation of melanoma cell metabolism. Work proposed in this project will closely integrate with studies outlined in Project 1 (UPR), Project 2 (PGC1) as with the two scientific Cores.